Summary

Abstract

Acamprosate (Campral® delayed-release tablet), a synthetic compound with a similar structure to that of the neurotransmitter GABA and the neuromodulator taurine, facilitates the maintenance of abstinence in detoxified alcohol-dependent patients. Although the precise mechanism(s) of action of the drug remains to be fully elucidated, it appears that it most likely involves beneficial modulation of the glutamatergic neurotransmitter system, including antagonism of the mGLu5 metabotropic glutamate receptor, to counteract the imbalance between the glutamatergic and GABAergic systems associated with chronic alcohol exposure and alcohol withdrawal.

In several double-blind, placebo-controlled trials of up to 12 months’ duration, acamprosate effectively maintained complete abstinence in detoxified alcohol-dependent patients, irrespective of disease severity or the type of psychosocial support. The drug showed better efficacy than placebo and was very well tolerated. Limited data from a relatively well designed trial indicate that the drug has similar efficacy to that of naltrexone and that combination therapy with these two agents provides better efficacy than acamprosate monotherapy, although multicentre direct head-to-head investigations are required to fully establish the potential of this combination. The drug may be particularly useful in those with hepatic impairment and/or liver disease. Thus, in combination with psychosocial and behavioural management programmes, acamprosate is a promising option for the maintenance of abstinence in alcohol-dependent patients after alcohol withdrawal.

Pharmacological Properties

Chronic alcohol exposure is thought to negatively alter the balance between the excitation of glutamatergic neurotransmitter systems and the inhibition of GABAergic neurotransmitter systems; the imbalance between these two systems is most likely associated with the development of tolerance to the effects of alcohol and alcohol-withdrawal symptomatology. Although acamprosate has a similar structure to that of GABA, in vitro and in vivo evidence suggests that key mechanism of action results from modification of the glutamatergic neurotransmitter system, particularly via modulation of activity at the NMDA receptor that is possibly mediated through modulation of the polyamine receptor site and/or via antagonism at the metabotropic mGlu5 receptor. In various animal models, acamprosate dose-dependently reduces acute and chronic alcohol self-administration and blocks the alcohol withdrawal-induced increase in glutamate. In in vitro studies, it reduced glutamate-induced neurotoxicity associated with alcohol withdrawal in cortical and hippocampal cell cultures and attenuated (±)-l-amino-cyclopentane-trans-l, 3-dicarboxylic acid (trans-ACPD)-induced neurotoxicity as seen in hippocampal slices from rats that had been chronically exposed to ethanol.

Peak plasma concentrations were achieved 5.5–7.3 hours after administration of oral acamprosate 1998 mg/day, with steady-state plasma concentrations achieved within 5 days. Bioavailability is low (absolute bioavailability ≈11%) and protein binding is negligible. The drug is widely distributed throughout the body (volume of distribution after intravenous administration is ≈1 L/kg [72–109L]); animal studies have shown that the drug can cross the blood-brain barrier. Acamprosate is not metabolised and is primarily excreted via the kidneys as unchanged drug, with a mean terminal elimination half-life of 18–33 hours. The pharmacokinetics of acamprosate are not affected by hepatic impairment. Total body and renal clearances of the drug are significantly reduced in renal impairment; dosage adjustments are required in patients with moderate renal impairment and the drug is contraindicated in those with severe renal impairment. No clinically relevant interactions are seen when the drug is coadministered with alcohol or medications used to treat alcohol dependence or common co-morbidities in this patient population, such as disulfiram, naltrexone, diazepam or imipramine.

Therapeutic Efficacy

Acamprosate, in combination with psychosocial therapy, was generally significantly more effective than placebo at maintaining complete abstinence in well designed trials of 3–12 months’ duration enrolling ≈3500 alcohol-dependent patients aged 18–65 years. In double-blind trials, treatment for 6 months’ with oral acamprosate 1332–1998 mg/day (dosage based on bodyweight) was generally associated with significantly more patients remaining completely abstinent (12–48% vs 11–33%), a longer mean cumulative abstinence duration (CAD; 61–110 vs 43–89 days), and a longer median time to first drink (TFD; 45–151 vs 15–61 days) than placebo. Where reported, after 6 months’ post-treatment follow-up, the beneficial effect of acamprosate on mean CAD was maintained. In addition, in a 3-month trial, acamprosate 1332 mg/day treatment was as effective as acamprosate 1998 mg/day in maintaining complete abstinence, with both dosages being more effective than placebo (acamprosate dosage given irrespective of bodyweight). Longer term placebo-controlled trials (11–12 months’ treatment) generally confirmed the superiority of acamprosate 1332–1998 mg/day over placebo in terms of abstinence endpoints. Significantly more acamprosate than placebo recipients remained completely abstinent (18–45% vs 7–25%) and the mean CAD was significantly longer in the acamprosate arms (175–225 vs 104–162 days). In general, the mean CAD remained significantly longer in acamprosate recipients during the 6- to 12-month post-treatment follow-up period.

Furthermore, coadministration of acamprosate and naltrexone was more effective in maintaining complete abstinence than acamprosate alone. In this 3-month, single-centre trial (n = 40 patients/group), the probability towards the first drink was significantly lower with acamprosate 1998 mg/day, naltrexone 50 mg/day or acamprosate plus naltrexone than with placebo in alcohol-dependent patients, with acamprosate plus naltrexone being more effective than acamprosate alone at preventing relapse to heavy drinking. In terms of maintaining complete abstinence (i.e. mean TFD; secondary endpoint), there was no intergroup difference between acamprosate 1665–1998 mg/day and naltrexone 50 mg/day in a 1-year single-blind study in alcohol-dependent patients; nevertheless, acamprosate was not as effective as naltrexone in terms of mean CAD or mean time to heavy drinking (primary endpoints).

Tolerability

Acamprosate is very well tolerated in abstinent alcohol-dependent patients. The incidence of adverse events with acamprosate was similar to that with placebo in clinical trials, with the exception of diarrhoea, which was the most frequently reported adverse event in either treatment group (16% vs 10%; no statistical analysis reported). Results from pooled pre- and postmarketing analyses in >7000 patients who received the drug for up to 1 year confirmed the good tolerability of acamprosate.

Data Selection

Sources: Medical literature published in any language since 1980 on acamprosate, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘acamprosate’. Searches were last updated 2 May 2005. Selection: Studies in patients with alcohol dependence who received acamprosate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.